Ciclesonid - ein neues inhalatives Kortikosteroid

Zusammenfassung

Ciclesonid (CIC) ist ein neues inhalatives Kortikosteroid (ICS), das als Prodrug über ein Lösungsaerosol inhaliert und zu 50 - 60 % in der Lunge deponiert wird. Dort wandeln Esterasen es in aktives des-Isobutyryl-Ciclesonid (des-CIC) um („On site”-Aktivierung). Hohe Lipophilie und Depotbildung in der Lunge verlängern die Wirkdauer und ermöglichen eine 1 × tägliche Inhalation. Klinische Studien mit Asthmapatienten belegen die Wirksamkeit bereits mit 80 µg/d CIC. Hohe Plasmaeiweißbindung und rasche Elimination aus dem Körper minimieren systemische Interaktionen, so dass CIC in Dosierungen bis zu 1280 - 1600 µg/d keinen Effekt auf Serum- und Urinkortisolwerte zeigte. Ciclesonid liegt im Oropharynx als inaktives Prodrug vor, daher wurde die ICS-typische orale Candidiasis so selten wie bei Plazebo-Gabe beobachtet. Im Vergleich zu anderen ICS besitzt CIC somit einen verbesserten therapeutischen Index und kann als Protagonist einer neuen, dritten Generation inhalativer Steroide bezeichnet werden.

Abstract

Ciclesonide is a novel inhaled corticosteroid delivered as inactive prodrug via a hydrofluoroalkane metered-dose inhaler with a deposition rate of 50 - 60 %. At its target sites, the lungs, ciclesonide is converted to an active metabolite, desisobutyryl-ciclesonide (des-CIC) [so-called on-site activation]. High lipophilicity and formation of local depot prolong pulmonary duration of action, explaining once-daily administration of ciclesonide. High protein binding and rapid clearance reduce systemic interactions. In long-term studies, ciclesonide at doses as high as 1280 - 1600 µg/d did not suppress biochemical markers of adrenal function. Since ciclesonide is not being activated in the oropharynx, the incidence of local adverse effects is comparable to that of placebo. Compared to other ICS, ciclesonide shows a improved therapeutic index and can, therefore, be regarded as prototype of a new, third generation of inhaled corticosteroids.

Literatur

• 1 Humbert M. Ciclesonide: a novel inhaled corticosteroid.  Expert Opin Investig Drugs. 2004;  13 1349-60
• 2 Reynolds N A, Scott L J. Ciclesonide.  Drugs. 2004;  64 511-519
• 3 Derendorf H. Relevant pharmacokinetic parameters for determining efficacy and safety in inhaled corticosteroids.  Eur Respir Rev. 2004;  13: 90 62-65
• 4 Bethke T. et al . High lung deposition of ciclesonide in 2D- and 3D-imaging.  Eur Respir J. 2002;  20 (Suppl. 38) 09
• 5 Tulic M K, Hamid Q. The Role of the Distal Lung in Asthma.  Seminars Respiratory Critical Care Medicine. 2002;  23 347-359
• 6 Lipworth B J, Jackson C M. Safety of inhaled and intranasal corticosteroids: lessons for the new millennium.  Drug Safety. 2000;  23 11-33
• 7 Belvisi M G. Preclinical pharmacology of ciclesonide.  Eur Respir Rev. 2004;  13: 90 60-68
• 8 Nave R. et al . Lower oropharyngeal deposition of inhaled ciclesonide via hydrofluoroalkane metered-dose inhaler compared with budesonide via chlorofluorocarbon metered-dose inhaler in healthy subjects.  Eur J Clin Pharmacol. 2005;  00 1-12
• 9 Richter K. Comparison of the oropharyngeal deposition of inhaled ciclesonide and fluticasone propionate in patients with asthma.  J Clin Pharmacol. 2005;  45 146-152
• 10 Mutch E. et al . Esterases involved in the hydrolysis of ciclesonide in human tissues.  Eur Respir J. 2003;  22 (suppl.45) 267
• 11 Nave R. et al . In vitro metabolism of ciclesonide in the human lung and liver as determined by use of precision-cut tissue slices.  Am J Respir Crit Care Med. 2003;  167 A771
• 12 Nave R. et al . Pharmacokinetics of [¹⁴C]ciclesonide after oral and intravenous administration to healthy subjects.  Clin Pharmacokinet. 2004;  43 479-486
• 13 Nave R. et al . Differences between pharmacokinetics of ciclesonide-active principle and budesonide following repeated dose inhalations.  Eur Respir J. 2003;  22 (Suppl 45) P333
• 14 Dubus J C. et al . Local side-effects of inhaled corticosteroids in asthmatic children: influence of drug, dose, age, and device.  Allergy. 2001;  56 944-948
• 15 Bousquet J. Safety and efficacy of inhaled corticosteroids.  Eur Respir Rev. 2004;  13: 90 69-72
• 16 Weinbrenner A. et al . Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide.  J Clin Endocrin Metab. 2002;  87 2160-2163
• 17 Lipworth B J. et al . Effect of ciclesonide and fluticasone on hypothalamic-pituitary-adrenal axis function in adults with mild-to-moderate persistent asthma.  Ann Allergy Asthma Immunol. 2005;  94 465-472
• 18 Derom E. et al . Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine 5`monophosphate in asthmatic patients.  Pulm Pharmacol Therapeut. 2005;  00 1-9
• 19 Szefler S. et al . High doses of the novel inhaled corticosteroid ciclesonide have no effect on HPA-axis function in patients with moderate-to-severe persistent asthma.  J Allergy Clin Immunol. 2003;  111 A590
• 20 Lee D KC. et al . Airway and systemic effects of hydrofluoroalkane formulations of high-dose ciclesonide and fluticasone in moderate persistent asthma.  Chest. 2005;  127 851-860
• 21 Price J. et al . Evaluating the effects of asthma therapy on childhood growth: What can be learnt from the published literature?.  Eur Respir J. 2002;  19 1179-1193
• 22 Agertoft L, Pedersen S. Short-term lower-leg growth rate and urine cortisol excretion in children treated with ciclesonide.  J Allergy Clin Immunol. 2005;  115 940-945
• 23 Stoeck M. et al . In vitro and in vivo anti-inflammatory activity of the new glucocorticoid ciclesonide.  J Pharmacol Exp Therapeut. 2004;  309 249-258
• 24 Leung S Y. et al . Effects of ciclesonide and fluticasone propionate on allergen-induced airway inflammation and remodeling features.  J Allergy Clin Immunol. 2005;  115 989-996
• 25 Lee D KC. et al . Effects of hydrofluoroalkane formulations of ciclesonide 400 µg once daily vs fluticasone 250 µg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma.  Br J Clin Pharmacol. 2004;  58 26-33
• 26 Taylor D A. et al . A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5`-monophosphate in asthmatic patients.  Am J Respir Crit Care Med. 1999;  160 237-243
• 27 Ukena D. et al . Ciclesonide significantly improves pulmonary function when compared with budesonide: a randomized 12-week study.  Eur Respir J. 2003;  22 (Suppl.45) 411
• 28 Buhl R. et al . Once daily ciclesonide is as effective as fluticasone propionate given twice daily in treating patients with asthma.  Am J Respir Crit Care Med. 2004;  169 A91
• 29 Postma D S. et al . Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or in the evening.  Eur Respir J. 2001;  17 1083-1088
• 30 Chapman K R. et al . Maintenance of asthma control by once-daily inhaled ciclesonide in adults with persistent asthma.  Allergy. 2005;  60 1-8